Chemokine is known as a basic protein having endogenous leukocyte chemotactic and activating activities and strong heparin-binding abilities. At present, it is considered that chemokine is related to not only the control of infiltration of specific leukocyte at the time of inflammations and immune responses but also the development and homing of lymphocyte under physiological conditions and migration of hemocyte precursor cells and somatic cells.
Differentiation, proliferation and cell death of hemocytes are controlled by various types of cytokine. In the living body, inflammations are found locally and differentiation, maturation and the like of lymphocytes are carried out at certain specific sites. That is, various necessary cells migrate into certain specified sites and accumulate therein to cause a series of inflammations and immune responses. Accordingly, migration of cells is also an indispensable phenomenon to lead to the immune system in addition to differentiation, proliferation and death of cells.
Migration of hemocytes in the living body starts firstly in the development stage by the shift of hematopoiesis started in the AGM (Aorta-Gonad-Mesonephros) region into permanent hematopoiesis in bone marrow via fetal liver. Furthermore, precursor cells of T cells and thymus dendritic cells migrate from the fetal liver into the bone marrow and then into the thymus gland and cytodifferentiate under thymus environment. The T cell which is subjected to clone selection migrates into secondary lymphoid tissues and takes part in an immune response in the periphery. The Langerhans's cell of the skin activated and differentiated by capturing an antigen migrates into the T cell region of a topical lymph node and activates naive T cell therein as a dendritic cell. The memory T cell demonstrates its homing ability again into the lymph node via lymphatic and blood vessels. Also, B cell, T cell in the intestinal epithelium, γδT cell, NKT cell and dendritic cell migrate from bone marrow without passing through the thymus gland and differentiate to take part in an immune response.
Chemokine is deeply related to the migration of these various cells. For example, CCR4 which is a receptor for MDC (Macrophage-derived chemokine) and TARC (Thymus and activation-regulated chemokine) is expressed in Th2 cell (see J. Immunol., 161, 5111 (1998)), and is known to play an important role in the migration of Th2 cell into topical sites where immune and inflammatory responses related to the Th2 cell is induced. In a mouse OVA-induced airway hypersensitivity model, an anti-MDC antibody suppressed the number of eosinophils accumulated in the lung interstitium, and suppressed airway hypersensitivity (see J. Immunol., 163, 403 (1999)). In a mouse OVA-induced airway hypersensitivity model, anti-TARC antibody suppressed infiltration of eosinophils and lymphocytes into the airway as well as airway hypersensitivity (see J. Immunol, 166, 2055 (2001)). In the investigation with Nc/Nga mouse, it was recognized that amounts of TARC and MDC have increased in the atopic dermatitis-like lesion site (see J. Clin. Invest., 104, 1097 (1999)). For CCR4 relation to human pathologic conditions, the number of CCR4 positive memory-T lymphocyte in peripheral blood increased depending on severity of dermatitis (see J. Allergy Clin. Immunol., 107, 353 (2001)), and the amount of TARC in the serum was also correlated to the severity in the atopic dermatitis patients (see J. Allergy Clin. Immunol., 107, 535 (2001)). The amount of TARC in the serum and the induced sputum also increased in the asthma patients (see Allergy, 57, 173 (2002)). MDC concentration in the blood was high in Th2 diseases such as atopic dermatitis and Sezary syndrome (see Eur. J. Immunol., 30, 201 (2000)).
There have been many reports suggesting correlation with other inflammatory diseases than allergic diseases, and CCR4 positive cell was accumulated selectively in the affected site of Lupus nephritis (see Arthritis Rheum., 46, 735 (2002)). Expression of TARC and MDC was high in the affected site of Crohn's disease (see Eur. Cytokine Netw., 12, 468 (2001)). CCR4 expression rose in the peripheral blood CD4 positive cells of systemic lupus erythematodes patients as compared with healthy persons (see J. Leuko., Biol., 70, 749 (2001)).
Furthermore, it has been known that chemokine play various roles in immune responses in addition to the migration of various cells. In the investigation with CCR4 deficient mouse, it was recognized that lethality by high dose LPS shock reduced as compared with wild type, and further, amounts of TNFα, IL-1β and MIP-1α also reduced in the blood after administration of LPS. Furthermore, in a rat fulminant hepatitis model (P.acnes+LPS), an anti-TARC antibody suppressed increase of the amount of ALT in the blood and increase of the expression amounts of TNFα and FasL in the liver and also improved lethality of the rats (see J. Clin. Invest., 102, 1933 (1998)). It was shown that CCR4 contributes to the binding of activated T cells and dendritic cells (see J. Immunol., 167, 4791 (2001)). Furthermore, TARC and MDC caused platelet aggregation mediated by CCR4 (see Thrombosis Research, 101, 279 (2001)), which is one of various physiological activities of chemokines and chemokine receptors.
Based on the above, chemokines and chemokine receptors are greatly related to the control of inflammation and/or immune responses through a mechanism in which they are expressed at certain specified periods in variously specific cells and its effector cells are accumulated in a region where chemokine is produced.
Acquired immunodeficiency syndrome (called AIDS) which is induced by human immunodeficiency virus (hereinafter referred to as “HIV”) is one of the diseases of which their therapeutic methods are most earnestly desired in recent years. Once infection with HIV is completed in a CD4-positive cell which is a principal target cell, HIV repeats its proliferation in the body of the patient and, sooner or later, completely destroys T cell which takes charge of the immunological function. During this process, the immunological function is gradually reduced to cause fever, diarrhea, lymph node enlargement and the like various immunodeficiency conditions which are apt to cause complications with pneumocystis carinii pneumonia and the like various opportunistic infections. Such conditions are the onset of AIDS, and it is well known that they induce and worsen Kaposi sarcoma and the like malignant tumors.
As the recent preventive and therapeutic methods for AIDS, attempts have been made to, e.g., (1) inhibit growth of HIV by the administration of a reverse transcriptase inhibitor or a protease inhibitor and (2) prevent or alleviate opportunistic infections by the administration of a drug having immunopotentiation activity.
Helper T cells which take charge of the central of immune system are mainly infected with HIV. It is known since 1985 that HIV uses the membrane protein CD4 expressing on the membrane of T cells in the infection (Cell, 52, 631 (1985)). The CD4 molecule is composed of 433 amino acid residues, and its expression can be found in macrophages, some B cells, vascular endothelial cells, Langerhans' cells in skin tissues, dendritic cells in lymphoid tissues, glia cells of the central nervous system and the like, in addition to the mature helper T cells. However, since it has been revealed that the infection with HIV is not completed by the CD4 molecule alone, a possibility has been suggested on the presence of factors other than the CD4 molecule, which are related to the infection of cells with HIV.
In 1996, a cell membrane protein called Fusin was identified as a factor other than the CD4 molecule, which is related to the HIV infection (Science, 272, 872 (1996)). It was confirmed that this Fusin molecule is a receptor (namely, CXCR4) of stromal derived factor-1 (hereinafter referred to as “SDF-1”). In addition, it was confirmed also in vitro that the SDF-1 specifically inhibits infection of T cell tropic (X4) HIV (Nature, 382, 829 (1996), Nature, 382, 833 (1996)). That is, it is considered that the HIV infection was inhibited by the binding of SDF-1 to CXCR4 preceding HIV, thereby depriving HIV of a foothold for infecting cells.
Also at that time, it was discovered that another chemokine receptor CCR5, which is a receptor of RANTES, MIP-1α and MIP-1β, is also used at the time of the infection with a macrophage tropic (R5) HIV (Science, 272, 1955 (1996)).
Accordingly, substances which can compete with CXCR4 and CCR5 for HIV, or which can bind to HIV virus thus causing the virus unable to bind to CXCR4 and CCR5, could become HIV infection inhibitors. Also, there is a case in which a low molecular compound initially discovered as an HIV infection inhibitor was actually a CXCR4 antagonist (Nature Medicine, 4, 72 (1998)).
Therefore, it is considered to use chemokine receptor antagonist as a preventive and/or therapeutic agent for inflammatory and/or allergic disease [for example, systemic inflammatory response syndrome (SIRS), anaphylaxis or anaphylactoid reaction, allergic vasculitis, transplant rejection reaction, hepatitis, nephritis, nephropathy, pancreatitis, rhinitis, arthritis, inflammatory ocular disease (e.g., conjunctivitis, etc.), inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease, eosinophilic gastroenteropathy, etc.), disease in cerebro and/or circulatory system (e.g., arteriosclerosis, thrombosis, ischemic/reperfusion disorder, restenosis, infarction, etc.), respiratory disease (e.g., acute respiratory distress syndrome (ARDS), asthma, pulmonary fibrosis, allergic broncho-pulmonary aspergillosis, etc.), dermatosis (e.g., dermatitis such as atopic dermatitis, psoriasis, contact dermatitis, eczema, urticaria and pruritus, and the like), autoimmune disease (e.g., multiple sclerosis, chronic articular rheumatism, systemic lupus erythematodes, Type I diabetes mellitus, glomerular nephritis, Sjoegren's syndrome, etc.), and the like], metabolism and/or endocrine system disease (e.g., diabetes mellitus, etc.), cancer disease [for example, malignant neoplasm such as leukemia, cancer and cancer metastasis, etc.), and the like], infection [for example, viral disease (e.g., human immunodeficiency virus infection, acquired immunodeficiency syndrome, SARS, etc.), and the like], and the like.
Until now, some compounds were disclosed as low molecular weight compounds having chemokine receptor antagonistic activity (see the specification of WO02/030357, WO02/030358, WO02/094264, WO03/051870, WO03/059893 and WO03/099773).
Also, the following sulfonamide compounds are known.
For example, the compound represented by formula (Y):

is known to be useful as an antiulcer agent (WO99/050237).
Also, the compound represented by formula (W):

is known to be useful as an antagonist and/or an agonist of PGE2 (WO98/027053). In this specification, 4-({[3-[(phenylsulfonyl)amino]-5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)benzoic acid is disclosed specifically (CAS No.: 209687-70-7).
Moreover, sulfonamide compounds of the following (1) to (17) are known:    (1) N-[3-(benzyloxy)pyridin-2-yl]-4-(trifluoromethoxy)benzenesulfonamide (CAS No.: 497060-26-1),    (2) N-[3-(benzyloxy)pyridin-2-yl]-4-fluorobenzenesulfonamide (CAS No.: 486441-58-1),    (3) N-{3-[(3,4-dichlorobenzyl)oxy]pyridin-2-yl}-4-propylbenzenesulfonamide (CAS No.: 307352-98-3),    (4) N-{3-[(3,4-dichlorobenzyl)oxy]pyridin-2-yl}-4-methoxybenzenesulfonamide (CAS No.: 307352-95-0),    (5) 4-bromo-N-{3-[(3,4-dichlorobenzyl)oxy]pyridin-2-yl}benzenesulfonamide (CAS No.: 307352-94-9),    (6) 4-chloro-N-{3-[(3,4-dichlorobenzyl)oxy]pyridin-2-yl}benzenesulfonamide (CAS No.: 307352-93-8),    (7) N-{3-[(3,4-dichlorobenzyl)oxy]pyridin-2-yl}-4-methylbenzenesulfonamide (CAS No.: 307352-92-7),    (8) N-{3-[(3,5-difluorobenzyl)oxy]pyridin-2-yl}-3,4-difluorobenzenesulfonamide (CAS No.: 307352-33-6),    (9) N-{3-[(3,5-difluorobenzyl)oxy]pyridin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (CAS No.: 307352-29-0),    (10) N-{3-[(3,5-difluorobenzyl)oxy]pyridin-2-yl}-4-pentylbenzenesulfonamide (CAS No.: 307352-21-2),    (11) N-{3-[(3,5-difluorobenzyl)oxy]pyridin-2-yl}-4-methylbenzenesulfonamide (CAS No.: 307352-20-1),    (12) N-{3-[(3,5-difluorobenzyl)oxy]pyridin-2-yl}-4-isopropylbenzenesulfonamide (CAS No.: 307352-11-0),    (13) N-{3-[(3,5-difluorobenzyl)oxy]pyridin-2-yl}-4-propylbenzenesulfonamide (CAS No.: 307352-10-9),    (14) 3-chloro-N-{3-[(3,5-difluorobenzyl)oxy]pyridin-2-yl}benzenesulfonamide (CAS No.: 307352-08-5),    (15) N-{3-[(3,5-difluorobenzyl)oxy]pyridin-2-yl}-4-methoxybenzenesulfonamide (CAS No.: 307352-07-4),    (16) N-{3-[(3,4-dichlorobenzyl)oxy]pyridin-2-yl}-4-isopropylbenzenesulfonamide (CAS No.: 307352-01-8), and    (17) N-{3-[(3,4-dichlorobenzyl)oxy]pyridin-2-yl}benzenesulfonamide (CAS No.: 307351-98-0).